Original article
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398
Peer reviewed article
Prospective study of accidental carbon
monoxide poisoning in 38 Swiss soldiers
Samuel Henz, Micha Maeder
Department of Internal Medicine, Cantonal Hospital of St. Gallen, Switzerland
Summary
Background: Carbon monoxide (CO) poisoning is associated with a wide range of non-specific
symptoms, whose time course and prognostic significance are ill defined.
Methods: We observed a large CO poisoning in
a homogenous cohort of 38 male recruits and compared their symptoms with those of 46 unexposed
controls from the same military unit. Incident and
prevalent symptoms were assessed by sequential
questionnaires.
Findings: Carboxyhaemoglobin (COHb) concentration extrapolated to the time of rescue was
30.4 ± 6.1%. Six recruits were initially unconscious,
and five others were unable to get out of their sleeping bags without help. Dizziness was the most common symptom within the first two weeks and was
reported in 92% of cases and 13% of controls, followed by headache (87% and 39%) and weakness
(76% and 26%). Most symptoms were already pres-
ent in the first hour, but vomiting, chest pain, and
hearing disorders typically had a delayed onset.
Headaches, cognitive impairment, and impaired
vision were the slowest to resolve. After an initial
maximum of 5.6 ± 2.9 symptoms (p <0.0001 for the
comparison with controls), cases reported 5.2 ± 2.5
symptoms at two days, 1.9 ± 2.3 symptoms at two
weeks, and 1.3 ± 1.6 symptoms at one year (p <0.0001
for decrease over time). Initial palpitations (p = 0.002)
and visual changes (p = 0.0003) were independent
predictors of a higher symptom score at one year.
Interpretation: In acute CO poisoning there are
immediate and delayed symptoms suggesting
different pathogenic mechanisms. Visual changes
and palpitations are independent predictors of
residual symptoms at one year.
Key words: carbon monoxide; poisoning; symptoms;
immediate; delayed; carboxyhaemoglobin
Introduction
Samuel Henz has
received funding
for other studies
by AstraZeneca and
Pfizer, this study
was not funded.
Both authors
declare that they
have no conflicts
of interest in this
particular study.
Carbon monoxide (CO) is a colourless, odourless, and non-irritating gas developing as a byproduct of the incomplete combustion of carboncontaining fuels. Accidental CO-poisoning is responsible for approximately 40 000 visits to the
emergency department and about 600 deaths annually in the United States [1, 2]. Endogenous CO
produced by the catabolism of haemoglobin acts as
a physiologic relaxant for smooth muscle cells [3].
It has further been identified as a neurotransmitter and seems to confer cytoprotection against oxidative stress in hypoxic or inflammatory conditions [4]. Major sources of exogenous CO include
motor vehicle exhaust fumes, defective heating
systems, tobacco smoke, and methylene chloride
[5]. The affinity of haemoglobin for CO is 200–250
times higher than for oxygen and carboxyhaemoglobin (COHb) is unable to transport oxygen. Carboxyhaemoglobin therefore accumulates during
exposure to even relatively small CO concentrations, which results in a consecutive decrease of
arterial oxygen transport capacity despite adequate
partial pressure of oxygen. Furthermore, CO
causes a shift of the oxygen-haemoglobin dissociation curve to the left resulting in impaired release
of oxygen at the tissue level and thus cellular
hypoxia [5–7]. Nevertheless, in experimental situations tissue hypoxia is only seen when COHb levels are very high (>70%). Thus, non-hypoxic mechanisms seem to contribute to the observed toxic effects [5, 6, 8]. Unfortunately, the clinical symptoms
of CO poisoning including headache, nausea, dizziness, and weakness are non-specific and may be
mistaken for viral illness in a considerable number
of cases, especially since viral infection and CO poisoning both peak during the winter months [5, 6,
9]. On the other hand it may be very hard to determine whether a symptom in a patient exposed to
CO is attributable to CO or not. Carboxyhaemoglobin levels often do not correlate with the severity of symptoms [5]. Furthermore, delayed onset of
neuropsychiatric symptoms is known to occur in
2–30% of patients [5]. In this paper we present a
quasi-experimental comparison of two groups of
healthy young soldiers, of which one was accidentally exposed to an exogenous source of CO.
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Patients and methods
Patients and questionnaires
Data handling
In October 2000, 38 male soldiers of the Swiss army
were accidentally exposed to CO. The group was sleeping
in a long stable directly adjacent to a small room in which
a gasoline-powered generator (5 kW, 3000 U/min) was
temporarily installed. One soldier was stationed outside as
a guard. At 01:30 a.m. when he was unable to wake up a
colleague for the change of guard, he gave alarm. The soldiers were immediately evacuated from the stable. Many
needed help, but all comatose spontaneously regained
consciousness within the next 15 minutes. Because of suspected CO poisoning all soldiers were transported to the
five nearest local hospitals, where they arrived between
5:15 and 6:30 a.m. Soldiers, who had been comatose were
treated with nasal oxygen during the transport. In the hospital oxygen was administered by facemask to all men and
they were observed for 6 to 24 hours depending on the
severity of their symptoms. One patient was transferred to
another hospital for hyperbaric oxygen treatment due to
transient limb paresthesias.
The largest group was brought to the Cantonal Hospital of St. Gallen, where one of the authors (S.H.) was responsible for their management and ad hoc created a questionnaire to assess onset, duration and severity of symptoms as well as potential risk factors for an unfavourable
clinical course. All men, including those treated in the
neighbouring hospitals were given the first questionnaire
two days after the accident. In this they were asked about
the following symptoms: headache, nausea, vomiting, palpitation, chest pain, breathlessness, visual problems, hearing disturbances, dizziness, confusion, weakness, clumsiness, or “other
symptoms”. Furthermore, each patient was asked about his
condition at the time of the alarm. Four conditions of increasing severity were offered: 0) ability to walk alone and
to help colleagues, 1) ability to walk out of the stable but
inability to help others, 2) consciousness but inability to
get out of the building without help, and 3) unconsciousness. Patients were also asked about a history of asthma
and cigarette smoking. At two weeks the soldiers were
given a second questionnaire concerning the 12-day timeperiod since completion of the first questionnaire. At one
year all cases were contacted by mail and asked to fill in a
third questionnaire relating to the period of the last month
and their present health condition. Vomiting, palpitation,
chest pain and breathlessness were not assessed at this timepoint; otherwise the questionnaire was identical. For the
majority of the 38 exposed soldiers blood pressure, heart
rate, temperature and the results of blood gas analyses on
admission could be extracted from the hospital charts. Informed consent was obtained from all patients and all controls. The accidental nature of the study however did not
allow acquiring formal approval by an ethics committee.
Since patients and controls were asked to report on
incidence, onset and duration of each symptom during the
respective time periods, it was possible to differentiate between the incidence of each symptom within these time
periods (ie 0 to 48 hours; 2 to 14 days, and month 12) and
the prevalence at the following time-points: 0, 1, 2, 3, 6,
and 12 hours, 1, 2, 3, 7, and 14 days, and at 1 year. Missing entries for incident symptoms were considered as the
absence of the respective symptom. If the symptom was
reported as incident but the data on onset and duration
were incomplete, the average onset and duration in the
cases with complete information were imputed for the
graphical presentation of the prevalence data. All statistical analyses were performed with the raw data however. A
symptom score was calculated by simply adding all reported symptoms at each time-point.
Controls
All 46 soldiers from a parallel military unit served as
controls. They were of comparable age and had undergone an identical training during the past 3 months, but
they had not been exposed to the exhaust of the generator. Two weeks after the accident they were asked to
anonymously complete the same questionnaire as their exposed colleagues, thus giving a subjective view of their
health status during the previous two weeks.
Blood gas analyses and carboxyhaemoglobin levels
For 17 patients an arterial blood gas sample was available without previous oxygen treatment. In 9 patients the
blood gas analysis was performed while the patient was
breathing oxygen by facemask. In 6 patients COHb levels
were only available from venous blood samples. From the
measured CO level (COa) we estimated the initial level
(COi) using the time between the time of alarm (t1) and
blood sampling (t2), the duration of oxygen therapy (dt)
and the published half-lives (HL) for COHb during respiration with air (HLair = 5 hours) and 100% oxygen
(HLox = 1 hour) respectively by the following equation:
COi = ( COa / e – ( ln 2 / HLox ) x dt ) / (e – ( ln 2 / HLair ) x ( t1–t2–dt) )
[5, 10].
Calculations were done assuming that all patients
who had initially been comatose had received oxygen therapy for 30 minutes during transport, and that those for
whom blood gas analysis was performed while receiving
oxygen supplements in the hospital had been treated for
15 minutes. Carboxyhaemoglobin levels in venous and arterial blood samples were considered to be equivalent [11].
Sleeping location during exposure
Each mans exact sleeping location on the two sides of
the long and narrow stable was reconstructed, and the approximate distance of each sleeping bag from the generator-room was expressed in meters. The soldiers were then
grouped as having slept close to (1–5 meters; n = 14), at a
medium distance (5–10 meters; n = 12), or distant (>10 meters; n = 12) from the generator.
Statistics
Statistical calculations were performed using the
statistical package SAS (SAS Institute, Cary, NC USA).
Continuous normally distributed data are presented as
means and standard deviations and were compared with
Student’s t-test. If normality was questionable, medians
and ranges are presented and the comparison was done
using Wilcoxon’s rank-sum test. Categorical variables
were compared using Fisher’s exact test. Multivariate
linear regression was used to search for predictors of a
higher COHb as well as a higher symptom-score at two
weeks and one year. In a stepwise procedure, variables
were included in the model if their p was <0.15, and they
remained in the model if their p was <0.05. The timecourse of the symptom-score in cases was analysed with
a mixed-procedures model for repetitive data using an
unrestricted covariance matrix and a restricted maximum
likelihood estimate.
Prospective study of accidental carbon monoxide poisoning in 38 Swiss soldiers
400
Results
Baseline characteristics
All 38 cases and 46 controls were male Caucasians. The age of the cases was 20.7 ± 1.3 years
and 8 (21%) reported a history of asthma. Cases
smoked a median of 15 (range 0–30), and controls
10 (0–60) cigarettes per day (table 1). In order to
keep the questionnaire as simple as possible, age
and co-morbidity of the control group was not explored. However male Swiss citizens must fulfil the
first part of their military service (recruit school)
between the age of nineteen and twenty-one years.
Table 1
Baseline characteristics
Baseline characteristics, and blood gas
analyses of cases at
admission.
Age (years)
20.7 ± 1.3 (n = 38)
Sex (male)
100% (n = 38)
Smoking
68% (n = 38)
Haemodynamics
Heart rate (bpm)
74.9 ± 12.8 (n = 27)
Systolic blood pressure (mm Hg)
135.0 ± 16.1 (n = 27)
Diastolic blood pressure (mm Hg)
72.2 ± 15.5 (n = 27)
Blood gas analyses
Haemoglobin (g/L)
150.6 ± 6.5 (n = 26)
Arterial pH
7.42 ± 0.04 (n = 28)
Arterial pO2 (mm Hg) *
113.2 ± 42.3 (n = 28)
Arterial pCO2 (mm Hg)
38.0 ± 4.3 (n = 28)
COHb (%) †
14.2 ± 3.0 (n = 32)
Extrapolated COHb (%) †
30.4 ± 6.1 (n = 32)
Bicarbonate (mmol/L) ‡
25.0 ± 1.4 (n = 30)
Lactate (mmol/L)
1.1 ± 0.4 (n = 22)
Data are given as mean ± standard deviation. Abbreviations:
pO2 = partial pressure of oxygen, pCO2 = partial pressure
of carbon dioxide, COHb = carboxyhaemoglobin; for calculation
of extrapolated COHb see text.
* oxygen administration in 9 cases. † venous samples in 6 cases.
‡ venous samples in 2 cases.
Figure 1
Point prevalence of
individual symptoms
in cases within two
weeks.
Time course of symptoms in cases
Six soldiers (16%) were initially unconscious,
five others (13%) could be woken up but were unable to get out of their sleeping bags without help,
and eight soldiers (21%) could leave the stable but
were unable to help others. Within the first day the
most prevalent symptoms were headache and
dizziness, followed by nausea and a sensation of
weakness. The prevalence of most symptoms
peaked at two to three hours (figure 1).
Latency to onset and duration
of symptoms in cases
The latency from the alarm to the onset of each
symptom differed considerably. Clumsiness and visual disturbances were already present when the
patient woke up from sleep or coma. Confusion,
dizziness, weakness, headache, palpitations and
shortness of breath were noted after a mean
latency of 10 to 20 minutes; nausea and hearing
impairment started within an hour, whereas vomiting and chest pain were late symptoms (figure 2).
Individual symptoms also greatly differed in
duration. Shivering was an early and quickly reversible, spontaneously reported symptom in two
patients. Shortness of breath, chest pain, vomiting,
palpitations and auditory impairment usually
lasted less than 12 hours, whereas nausea, weakness, dizziness, and clumsiness generally lasted up
to one day. Headaches, visual changes, and a sensation of confusion often persisted much longer
(figure 3).
Differences between cases and controls:
types of symptoms
Due to the variation within onset and duration
of each symptom the prevalence changed considerably over time. For the comparison with controls
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401
Figure 2
Latency time from
alarm to start of each
symptom (hours).
Boxplots show 10th,
25th, 50th, 75th, and
90th percentiles
as well as outliers
(circle) but not
extremes. N denotes
the number of subjects who reported
the latency.
Figure 3
Duration of symptoms (days) excluding the time to onset.
Boxplots show 10th,
25th, 50th, 75th, and
90th percentiles
as well as outliers
(circles) but not
extremes. N denotes
the number of subjects who reported
the duration.
we therefore used the cumulative incidence of reported symptoms within two weeks after exposure.
These incidence data are typically higher than the
peak prevalence.
Dizziness had the highest incidence within the
first two weeks following exposure (reported in
92% of cases and 13% of controls), followed by
headache, weakness, nausea, breathlessness, chest
pain, visual changes, confusion, palpitations, auditory symptoms, clumsiness, and vomiting (table 2).
Differences between cases and controls:
number of symptoms
After an initial maximum of 5.6 ± 2.9 symptoms, cases reported on average 5.2 ± 2.5 symptoms at two days, 1.9 ± 2.3 symptoms at two weeks
and 1.3 ± 1.6 symptoms at one year (p <0.0001
for the decrease over time). Controls reported
1.7 ± 1.7 symptoms (p <0.0001 for the comparison
with the initial symptoms in cases).
Carboxyhaemoglobin levels
Arterial (n = 28) or venous (n = 6) blood gas
samples were drawn 346 ± 57 minutes after the
end of exposure. In 9 cases the samples were obtained shortly after the start of oxygen treatment.
The mean uncorrected COHb level (n = 32) was
14.2 ± 3.0%. The mean extrapolated COHb level
for the time of rescue was 30.4 ± 6.1% (table 1).
The extrapolated COHb level was on average
1.1% higher for each package of cigarettes smoked
per day (p = not significant [ns]), and 3% higher
for each of the three degrees of increasing coma
severity (p <0.001). Yet there was no association between COHb levels and the type or number of
other symptoms at any time point.
Contrary to our expectations, the highest
COHb levels were not found in patients lying closest to the generator, rather the levels significantly
increased by 0.5% for each meter further away
from the generator (p = 0.007, adjusted for smok-
402
Prospective study of accidental carbon monoxide poisoning in 38 Swiss soldiers
Table 2
Symptom
Cumulative Incidence
Cumulative incidence
of symptoms within
two weeks after
exposure in cases
and controls.
Cases
Controls
Dizziness
92%
Headache
Weakness
Table 3
Characteristics of
soldiers reporting
more than one
symptom at one year.
Odds
Ratio
95% Confidence
Interval
P Value
13%
78
18–334
<0.0001
87%
39%
10
3.4–31
<0.0001
76%
26%
9.1
3.4–25
<0.0001
Nausea
71%
15%
14
4.7–40
<0.0001
Shortness of breath
36%
11%
4.7
1.5–15
0.005
Chest pain
34%
15%
2.9
1.02–8.3
0.04
Visual changes
34%
7%
7.5
1.9–29
0.002
Confusion
29%
11%
3.3
1.04–11
0.04
Palpitations
24%
4%
6.8
1.4–34
0.009
Auditory disturbances
24%
2%
4.0
1.7–116
0.002
Clumsiness
24%
7%
4.4
1.1–18
0.03
Vomiting
18%
7%
3.2
0.8–14
0.09
Loss of consciousness
16%
0%
<0.0001
Score
2 days
score
2 weeks
score
1 year
COHb
coma
smoker
residual symptoms after one year
8
*
6
44.4
3
Yes
headache, dizziness, weakness,
clumsiness, fatigue, nausea
8
2
4
31.7
2
Yes
headache, visual changes, dizziness, nausea
9
8
3
*
1
Yes
headache, dizziness, nausea
6
3
3
26.6
0
Yes
headache, auditory disturbances,
lack of energy
8
3
3
26.5
1
No
headache, dizziness, confusion
6
4
2
28.2
0
Yes
visual changes, auditory disturbances
9
8
2
29.6
1
Yes
confusion, reduced strength
6
4
2
21.7
0
Yes
headache, confusion
7
7
2
27.0
3
No
headache, confusion
The scores denote the added number of symptoms within the first two days, after two weeks, and after
one year. COHb denotes extrapolated carboxyhaemoglobin levels. Coma is graded as follows: “0” = ability
to walk alone and to help his colleagues, “1” = ability to walk out of the stable, but inability to help others,
“2” = consciousness but inability to get out of the building without help, and “3” = unconsciousness.
* = data not available
ing). This effect however was lost after about 5 meters. If the soldiers were divided into three subgroups according to their distance from the CO
source, it became evident that, compared to soldiers at the furthest end of the stable, COHb-levels were on average 6.3% lower in the group closest to the generator (p = 0.02), but only 1.8% lower
(p = ns) for those sleeping in the middle section.
Outcome predictors
Follow-up information at one year was available for 25 persons. Eleven of them (44%) reported no symptoms at all, five (20%) reported one
symptom (invariably intermittent headaches), four
others (16%) had two symptoms, three persons
(12%) had three, one (4%) had four symptoms, and
another one (4%) reported six symptoms. Charac-
teristics of the soldiers with more than one residual symptom at one year are presented in table 3.
According to the information system of the Swiss
army (PISA) all soldiers, who did not respond to
the last questionnaire, were alive and still regular
members of the army two years after the exposure.
In a multivariate regression model initial
palpitations (p = 0.002) and visual disturbances
(p = 0.0003) were independent predictors of a
higher symptom score at one year. The presence
or absence of visual symptoms was the better predictor for at least one late symptom other than
headache with a sensitivity of 67% and a specificity
of 87%, whereas the presence or absence of palpitations had a sensitivity of only 44% and a specificity of 80%.
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Discussion
Carbon monoxide poisoning causes a wide
spectrum of acute symptoms ranging from mild
(constitutional symptoms similar to viral illness) to
severe and even fatal disease (respiratory depression, coma, cerebral oedema) [5]. With 11 (29%)
patients unconscious or unable to walk, the poisoning in our study is comparable to other large
series in the literature [9, 12, 13]. The strength of
our observation lies in the highly uniform cohort
of otherwise healthy young men and the equally
homogeneous control group, which converts this
accidental exposure into a quasi-experimental
study, in which the effects of CO exposure can
be analysed without interference from other
diseases. Since most patients could be sequentially
assessed, starting only a few hours after exposure,
we were able to prospectively evaluate the time
course and the prognostic significance of each
symptom.
The time to onset of each symptom varied considerably. Coma, the inability to walk, shivering,
clumsiness and visual disturbances were invariably
present from the very beginning, whereas auditory
impairment, nausea and especially chest pain or
vomiting often developed after a latency period of
several hours. Although we cannot exclude that
some more subtle symptoms were already present
earlier but were only noted when more life-threatening symptoms diminished, these variable latencies to symptom onset are most likely due to different pathogenetic mechanisms. We postulate
that early and rapidly reversible symptoms are
more likely to be caused by direct toxic effects of
CO or COHb-associated tissue hypoxia, whereas
delayed symptoms may have other causes, such as
brain oedema, localised vasomotor phenomena,
secondary radical damage, or possibly psychological distress.
Coma or the inability to move was significantly
correlated with higher COHb levels. These symptoms rapidly improved within a few minutes after
rescue in all patients. Nonetheless given the long
half-life of COHb (about five hours without oxygen therapy) neither the initial degree of coma nor
this quick recovery can be explained by the degree
of tissue oxygenation alone. From animal experiments we know that the cerebral metabolic rate
for oxygen does not decrease below 90% of baseline until about 27% COHb is reached [14, 15].
Since many of our patients were below this level,
cerebral oxygen supply should have been more
than sufficient. In the 1940s, Drabkin et al. noted
that dogs which received blood replacement to
acutely produce 75% COHb showed none of the
characteristic signs of anoxia as seen in dogs which
inhale CO to the same level of saturation [16]. The
non-haemoglobin bound fraction of CO thus must
have anaesthetic properties beyond its ability to induce hypoxia. The quick resolution of this anaesthetic effect in our patients is an argument for a
more rapid dissociation from its site of anaesthetic
action than from haemoglobin. The cellular target
of CO’s anaesthetic action is not known. Potential
candidates are intracellular haeme proteins, such
as a recently described neuroglobin [17, 18].
Theoretically, CO may interfere with cellular respiration by binding to mitochondrial cytochrome
c oxidase, but this is probably not clinically important since the affinity of cytochrome oxidase for
CO is much lower than for oxygen [19]. Some
researchers have also argued that CO may have
direct neuropsychiatric effects by deranging dopaminergic and serotoninergic neural functions
[20].
Muscle weakness could secondarily result from
the same neurodepressive effects, but also from a
direct binding of CO to myoglobin (Mb). Myoglobin is a respiratory haeme protein of muscle cells
and has an even higher relative affinity for CO over
oxygen than haemoglobin. Since functional Mb is
required for maximal oxygen uptake by the muscle
respiratory chain, muscle performance is reduced
as CO binds to Mb [7]. A significant impairment
of muscle oxidative phosophorylation is therefore
already found at COHb levels between 20 and
40% [18]. This was the typical range in our patients, 76% of whom reported a feeling of weakness.
Other early symptoms were clumsiness and
visual disturbances. Endogenous CO together with
nitric oxide (NO) is a physiologic modulator of
retinal signal transduction [21]. Visual disturbances could thus result from an overwhelming
stimulation of this signalling pathway. In more severe intoxication retinal haemorrhage and papilloedema are common [22, 23]. However, deterioration of visual acuity can occur after several days
and may respond to treatment with hyperbaric
oxygen [24]. Similar to the brain the retina also
contains high levels of neuroglobin [25]. Comparable to the role of Mb in muscle cells, this
extravascular haeme protein may facilitate oxygen
delivery to mitochondria and defend against oxidative stress [26]. Since neuroglobin has a high
affinity for CO, intoxication could interfere with
retinal oxygen delivery and antioxidative defence
mechanisms [27].
Headaches, nausea, and vomiting often developed with a latency period of several hours. This
finding is in sharp contrast with the steadily declining blood and tissue contents of CO and requires
other explanations than COHb levels. The similarity between CO intoxication and migraine is
striking: Hampson & Hampson found no discriminating pattern in CO intoxication as opposed to
other causes of headache [28]. Brain tissue is
largely insensitive, but pain can be generated
by cranial vessels or the dura mater [29]. In migraine the characteristic symptoms are preceded
by a phase of increased cerebral blood flow, which
Prospective study of accidental carbon monoxide poisoning in 38 Swiss soldiers
is then followed by oligaemia and depressed neuronal function [29]. In experimental CO intoxication cerebral blood flow also increases in order to
correct for the degree of hypoxaemia [30]. This
autoregulatory rise in cerebral blood flow is a consequence of vascular smooth muscle activation of
calcium dependent potassium channels through
CO, but seems to include mechanisms mediated
by NO [31, 32]. Nitric oxide can induce delayed,
slowly developing activation of central trigeminal
neurons in an experimental model of migraine
[33]. The often late onset of headache and nausea
in our patients could therefore be caused by similar vascular and humoral mechanisms as in migraine. Brain oedema, which in fatal cases can
progress for up to 48 hours [34], may aggravate
these symptoms in severe CO intoxication.
Delayed neuropsychiatric symptoms after apparent recovery from acute CO intoxication are estimated to occur in 2 to 30% of victims and have
been reported 3 to 240 days after exposure [5].
Mimura et al. described the long-term follow-up
of 156 patients after severe CO poisoning in a mine
[35]. Most patients reported memory deficits, followed by irritability, headaches, insomnia, and
limb pain. Many patients also showed personality
changes and extrapyramidal movement disorders.
In our series nine patients (36% of those for whom
information was available) reported persistent
neuropsychiatric symptoms other than headaches
after one year. All of these had also been symptomatic at two days and two weeks (table 3). Annane
et al. reported dizziness before admission and
headaches upon hospital admission as significantly
associated with persistent neurological symptoms
after one month [36]. Given the almost invariable
initial presence of these two symptoms, their
positive predictive value is very low. Most other
authors were unable to identify a clinical or
laboratory parameter, which could predict the
occurrence of late sequelae [5]. We found initial
palpitations (p = 0.002) or visual disturbances
(p = 0.0003) to be independent predictors of residual neuropsychiatric symptoms after one year. The
presence of visual symptoms was the best single
predictor for at least one late neuropsychological
symptom (other than headache) after one year. It
had a sensitivity of 67% and a specificity of 87%.
Several explanations for these delayed neuropsychological symptoms have been proposed.
In diffusion MRI reversible white matter-lesions,
especially in the basal ganglia, can be observed
during acute CO intoxication [37, 38]. Despite
a global increase in cerebral blood-flow during
CO intoxication [39], SPECT-studies typically
demonstrate regional hypoperfusion in the basal
ganglia and brain cortex during the reoxygenation
phase [40]. Carbon monoxide induces oxidative
damage including brain lipid peroxidation and
polymorphonuclear leukocyte sequestration in the
cerebral vasculature [41]. Nitric oxide induced by
CO is at least partially responsible for these events
404
[41]. Apoptotic cell death was found in some animal models of CO intoxication [42]. CO poisoning also causes elevations of the excitatory amino
acid glutamate and dopamine in rats [42]. In experimental CO poisoning, the elevation of glutamate
has been linked to a delayed type of amnesia: loss
of neurons in the hippocampus of mice and loss of
glutamate-dependent cells in the inner ear of rats
[18, 43]. One may therefore speculate that in addition to hypoxia inhomogeneous perfusion and a
cascade of oxidative and neuroexcitatory events
following CO intoxication could confer a higher
vulnerability to predisposed brain regions.
Chest pain started after a median of 90 minutes
and rarely lasted more than two days. Carbon
monoxide acts as a physiologic relaxant for vascular smooth muscle cells including coronary arteries [44]. This effect is also mediated by NO [45].
At first we would therefore consider myocardial
ischaemia an unlikely explanation of chest pain,
especially among very young trained soldiers.
Nevertheless, chronic professional CO exposure
is an independent risk factor for mortality from
ischaemic heart disease [46], and in patients
with chronic coronary disease CO increases the
likelihood of angina [47–49]. Moreover, several
patients with normal coronaries have been described with acute myocardial infarction in acute
CO intoxication [50–52]. In CO poisoning a sharp
reduction in total peripheral arterial resistance and
a lability of blood pressure is found in humans [53].
The combination of coronary steal phenomena
due to hypotension, decreased oxygen transporting capacity of the blood due to CO-Hb, decreased
intracellular oxygen utilization due to CO-myoglobin, impaired mitochondrial function [54, 55]
together with increased cardiac output to correct
for whole body hypoxaemia may lead to myocardial ischaemia. Increased sympathetic tone
(eg resulting from panic in our patients) may increase myocardial oxygen demand, and hyperventilation could provoke coronary spasms both
of which may aggravate myocardial ischaemia. Indeed inhomogeneous venous myocardial oxygen
saturation was found in a canine model of CO
exposure [44] suggesting heterogeneous oxygen
consumption and possibly regional myocardial
ischaemia.
Our main goal was to describe the time course
and prognostic significance of each symptom in
acute CO-intoxication. Nevertheless, the unexpected finding of 0.5% higher extrapolated COHb
each meter further away from the generator merits a comment. This effect was most pronounced
within the first five meters from the generator and
suggests a causal role for the convection of hot exhausts in the room. Since the extraction of CO
from inspired air is nearly complete, the persons,
who first came in contact with the gas, ie those
lying further away, may have served as biological
sinks and may thus have partially protected their
colleagues.
S W I S S M E D W K LY 2 0 0 5 ; 1 3 5 : 3 9 8 – 4 0 6 · w w w . s m w . c h
Study limitations
The questionnaire was created within hours
after the arrival of the soldiers in the emergency
room in order to prospectively evaluate symptoms
of CO exposure. The collection of clinical data
such as the duration of oxygen therapy was, however, done retrospectively and is therefore incomplete. The advantage of this very homogeneous
population has a drawback: the degree to which
one can generalise beyond a population of young
men is questionable. Since the symptoms of our
patients were very similar to those of other studies, which included persons of both genders and a
larger age-range, broader validity is however to be
expected.
405
Acknowledgment: For assistance with data collection
we are indebted to the military physician, David Simonett, MD, and to the chiefs of the medical departments
of our neighbouring hospitals: Paul-Josef Hangartner,
MD, Altstätten, Urs Trümpler, MD, Wil, Yves Crippa,
MD, Grabs, and Jürg Winnewisser, MD, Wattwil.
We further thank Renato L. Galeazzi, MD, Professor of
Medicine, St. Gallen, and Karl Schimke, St. Gallen, for
helpful remarks concerning the manuscript.
Correspondence:
Samuel Henz, MD MPH
Department of Internal Medicin
Hospital of St. Gallen
Rorschacherstrasse 95
CH-9007 St. Gallen
Switzerland
E-Mail: [email protected]
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